Preclinical studies showed a synergistic antileukemia activity with combination of selective XPO1 inhibitor selinexor (SEL) and venetoclax (VEN), with potential to overcome VEN resistance by reducing the anti-apoptotic protein MCL1. In an investigator-sponsored, open-label, phase Ib study (NCT03955783), adult patients with relapsed or refractory acute myeloid leukemia (R/R AML) were enrolled. After the dose-escalation phase, SEL 80 mg po weekly plus VEN 400 mg/day following ramp-up was deemed the recommended phase II dose. Responses were assessed with IWG2003 and ELN 2022 criteria. Nineteen patients with R/R AML were enrolled. Median age at enrollment was 67.2 (range, 21.1-83.8) years. Overall, patients received median of 3 (range, 1-5) prior lines of therapy. The most common grade 3-5 treatment emergent adverse events (TEAE) were anemia (39%), neutropenia (33%), febrile neutropenia (28%), and thrombocytopenia (28%). Overall, the response rate with SEL-VEN was 21%. Two (11%) patients, one with prior allo-HSCT and one with prior VEN and both treated with SEL 80 mg/week, experienced complete remissions, with duration of response of 7 and 9.1 months, respectively. After a median follow up of 3.0 (range, 0.6-15.4) months, median event-free survival was 2.4 (95% CI: 1.9-12.1) months and median overall survival was 6.4 (95% CI: 2.5-12.1) months. In conclusion, SEL-VEN was feasible and active in a heavily pretreated AML cohort, with no new toxicity signal, but survival outcomes remained poor. The second-generation XPO1-inhibitor eltanexor, combined with VEN may further improve outcomes in VEN resistant AML in an ongoing study (NCT06399640).
Ball et al. (Sun,) studied this question.